Rab27A-dependent transfer of CD11c+ cell exosomes regulate gut immunity

Abstract

Abstract Intercellular communication is critical for maintaining homeostasis in mammalian organ systems, including the gastrointestinal (GI) tract. Exosomes are small nanoscale lipid extracellular vesicles that mediate communication between a wide variety of cell types. Notably, the roles played by immune cell exosomes in regulating homeostasis and inflammation in the GI tract are largely uncharacterized. Here, we describe an unknown mechanism of exosome-mediated immune regulation within the GI tract. By generating novel mouse strains, we demonstrate that disruption of exosome signaling via the deletion of Rab27a in CD11c+ myeloid cells exacerbates colitis, which is reversed through administration of dendritic cell (DC)-derived exosomes. Profiling small noncoding RNAs within exosomes from colonic tissues revealed a distinct subset of microRNAs (miRNAs) carried by both gut- and DC-derived exosomes. Among the DC-enriched exosomal miRNAs, miR-146a was transferred from gut CD11c+ cells to myeloid and T cells through a Rab27-dependent mechanism to decrease macrophage-mediated inflammation during colitis. Clinically, RAB27A is also expressed at lower levels in a cohort of ulcerative colitis patients versus healthy controls. Together, this work reveals an exosome-mediated modulatory mechanism of gut inflammation, paving the way for exosomes containing miRNA cargo as a potential therapeutic for inflammatory bowel disease. Supported by National Institutes of Health Grants T32 AI 138945-1 (K.M.B.) and AI123106-01A1 (R.M.O.)